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Role of the Highly Conserved LWYIK Motif of the HIV-1 Transmembrane Protein gp41 in Env-mediated Membrane Fusion. Steve S.-L. Chen and Woan-Eng Chan Institute of Biomedical Sciences Academia Sinica Taipei, Taiwan R.O.C. August 14, 2006 2006 International AIDS Conference. FP. NHR. CHR.
Steve S.-L. Chen and Woan-Eng Chan
Institute of Biomedical Sciences
August 14, 2006
2006 International AIDS Conference
The Tryptophan-rich domain
located immediately proximal to the TM region
Li and Papadopoulos: Cholesterol-binding motif: L/V-(X)1-5-Y-(X)1-5-R/K
Vincent et al.Identification of a conserved domain of the HIV-1 transmembrane protein gp41 which interacts with cholesteryl groups. Biochim. Biophys. Acta 1567: 157-164, 2002
in CD4+ CEM-SS cells
one-cycle virus infectivities: on an
cat gene-harboring reporter cell line, H938
significant effects on Env precursor synthesis,
processing, or Env incorporation into the virus
Mutations in the LWYIK motif do not affect cell surface expression or CD4-binding ability of the Env
All of the mutant proteins are able to self-assemble into an oligomeric structure
their trans-complementation abilities
on the Env membrane fusion ability
apparent effects on Env association with
Fusion pore enlargement
inhibit cytosolic dye transfer
Env Membrane Virus
Incorporation fusion Infectivity Dye transfer
WT Normal 100% 100% +
665~682 Greatly Reduced Abrogated Greatly reduced -
W(1~5)A Greatly Reduced Abrogated Greatly reduced +
W(1~3)A Greatly Reduced Abrogated Greatly reduced
678~682 Greatly Reduced 20% Greatly reduced +
666~670 Greatly Reduced 20% Greatly reduced
LWYIK Normal - 10% No cytosolic mixing no cytosolic mixing
YI Normal - 10% Reduced cytosolic
IK Normal - 10% Reduced cytosolic
Institute of Biomedical Sciences, Academia Sinica:
Animal Technology Institute Taiwan:
Supported by :
Academia Sinica and
National Health Research Institute
Only the functional pre-TM sequence:
1), adopts helical structures in solution and in membranes;
2), forms homo-oligomers in solution and membranes; and
3), inhibits gp41-induced cell-cell fusion.
These data support two roles for gp41 aromatic-rich pretransmembrane sequence:
1), oligomerization of gp41; and 2), immersion into the viral membrane interface.
T. Suarez et al. FEBS Lett. 477:145-149, 2000
A functional peptide can induce vesicle leakage and lipid mixing.
A sequence representing a defective gp41 phenotype unable to mediate both cell–cell
fusion and virus entry, is equally unable to induce vesicle fusion, and adopted a
non-helical conformation in the membrane.
Therefore, membrane perturbation and adoption of the α-helical conformation by this
gp41 region might be functionally meaningful.
Salzwedel et al. J. Virol. 73:2469-2480, 1999
The multiple effects of various mutations in this region on membrane
fusion, Env incorporation into the virus, and virus infectivity suggest that different
residues or sequences in this motif may still play disparate functions in HIV-1
infection and that multiple sequences in this motif may contribute synergistically to
Fusion of outer leafets
Fusion of inner leaflets
Fusion pore formation and enlargement